Regulation of PTGS2 by TGF-beta in Human Uterine Stromal Cells Through Ubiquitination via Upregulation of MAN1B1.
Bibliographic record
Abstract
TGF-β is known to be secreted by endometrial epithelial cells, which are in close proximity with stromal cells. Both the epithelial cells and stromal cells synthesize and secrete prostaglandins (PGs) at different time during the menstrual cycle and pregnancy. Cycloxygenases (PTGS1 and PTGS2) are the rate-limiting enzymes responsible for the synthesis of various PGs. The aim of the present study was to investigate the expression and regulation of PTGS1 and PTGS2 in the presence of TGF-β isoforms in human uterine stromal (Hend2) cells. Transcript levels were measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Protein levels were analyzed by western blotting and immunofluorescence. Prostaglandin E2 (PGE2) was measured using enzyme immunoassay (EIA). The results revealed that there was an increase in the levels of phosphorylated Smad2 and Smad3 upon treatment of Hend2 cells with all the three TGF-β isoforms, thus indicating that Smad pathway was activated by TGF-β isoforms in these cells. No change in the protein levels of total Smad2/3 was observed. Expression of PTGS2 was significantly decreased at the protein level in the presence of TGF-β isoforms. Accordingly, PGE2 levels were also decreased by TGF-β treatment. To determine if PTGS2 decrease was due to protein degradation, PTGS2 expression was further studied in the presence of proteasomal inhibitor, MG-132 and MAN1B1 (mannosidase, alpha, class 1B, member 1) inhibitor, kifunensine. Pre-treatment with these inhibitors restored the levels of PTGS2 and PGE2 suggesting that TGF-β regulate the expression of PTGS2 through ER-associated degradation (ERAD) system by 26S proteasome degradation. Furthermore, up regulation of MAN1B1 at both transcript and protein level by TGF-β isoforms treatment, suggests the involvement of MAN1B1 in promoting ubiquitin mediated proteasomal degradation of PTGS2. Collectively, these findings strongly indicate that the TGF-β isoforms induce 26S proteasome mediated PTGS2 degradation in human uterine stromal cells through the upregulation of MAN1B1 and this mechanism might be a key system to control prostaglandins secretion during the different reproductive processes. (platform)
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".